The present invention relates to compositions and methods of achieving a therapeutic effect including the treatment of congestive heart failure or hypertension in an animal, preferably a mammal including a human subject or a companion animal, using a corticotropin releasing factor (CRF) antagonist, preferably in synergistic combination with a renin-angiotensin system (RAS) inhibitor.
In preferred embodiments of the compositions and methods of this invention, the CRF antagonists comprise compounds of structural formula I or II, including the pharmaceutically acceptable salts thereof, as defined hereinbelow.
The compounds of formula I or II, their pharmaceutically acceptable salts, and methods of preparing such compounds and salts are disclosed in commonly assigned PCT publication numbers WO 95/34563, WO 95/33750, WO 94/13676, WO 94/13677 and European patent application number EP 773 023. Each of the applications corresponding to PCT publication numbers WO 95/34563, WO 95/33750, WO 94/13676 and WO 94/13677 designate, inter alia, the United States and are incorporated herein by reference in their entirety.
The foregoing PCT and EP publications refer to the use of the compounds of formula I or II, and their pharmaceutically acceptable salts, in the treatment of illnesses induced or facilitated by CRF and in the treatment of anxiety, cardiovascular diseases, depression, fatigue syndrome, gastrointestinal diseases, headache, pain, cancer, immune dysfunction, hemorrhagic stress, drug addiction, drug and alcohol withdrawal symptoms, fertility problems, stress-induced psychotic episodes, neurodegenerative diseases such as Alzheimer""s disease; irritable bowel syndrome including Crohn""s disease, spastic colon and irritable colon; eating disorders such as anorexia nervosa; and inflammatory disorders such as arthritis, asthma and allergies. Other CRF antagonists useful in the compositions and methods of this invention are referred to in commonly assigned PCT publication numbers WO 95/33727, WO 94/13644 and WO 94/13643. Each of the applications corresponding to PCT publication numbers WO 95/33727, WO 94/13644 and WO 94/13643 designate, inter alia, the United States and are incorporated herein by reference in their entirety.
RAS inhibitors useful in the practice of the instant invention include renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-II (A-II) antagonists. Such RAS inhibitors are useful in the lowering of blood pressure in mammals and find utility in the treatment of congestive heart failure as well as other therapeutic effects. Specific RAS inhibitors useful in the practice of the instant invention are disclosed and referenced in detail hereinbelow.
Until the invention described herein, there was no report of use of or intent to use a CRF antagonist together with a RAS inhibitor to achieve any therapeutic effect including the synergistic treatment of congestive heart failure or hypertension.
Further, until this invention, there was no report of a pharmaceutical composition comprising a CRF antagonist together with a RAS inhibitor, nor of the use or intent to use such a composition in the synergistic therapeutic treatment of any condition including congestive heart failure or hypertension.
This invention relates to compositions and methods useful in achieving therapeutic effects such as the synergistic treatment of congestive heart failure or hypertension, which compositions preferably comprise synergistic therapeutically effective amounts of a CRF antagonist, a RAS inhibitor and a pharmaceutically acceptable carrier or diluent and which methods preferably comprise administering to an animal, preferably a mammal including a human subject or a companion animal in need of such treatment, synergistic therapeutically effective amounts of a CRF antagonist and a RAS inhibitor.
Preferably, the invention relates to the use of a CRF antagonist in combination with a RAS inhibitor selected from the group consisting of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II antagonist and a renin inhibitor. More preferably, the renin angiotensin system inhibitor is a compound selected from the group consisting of benazeprilat, captopril, enalapril, lisinopril, losartan, valsartan, irbesartan, candesartan, telmisartan, tasosartan and eprosartan.
A preferred class of CRF antagonists comprises compounds of structural formula I or II, below, 
including the pharmaceutically acceptable salts thereof, wherein the dashed line represents an optional double bond, and A, B, D, E, Y, Z, R3, R4 and R5 are as defined hereinbelow.
The present invention relates to compositions and methods of achieving a therapeutic effect including, but not limited to, the treatment of congestive heart failure or hypertension in an animal, preferably a mammal including a human subject or a companion animal, using a corticotropin releasing factor (CRF) antagonist, preferably in synergistic combination, with a renin-angiotensin system (RAS) inhibitor.
A first preferred aspect of the instant invention relates to compositions and methods for treating congestive heart failure, which compositions comprise synergistically effective amounts of a CRF antagonist, a RAS inhibitor and a pharmaceutically acceptable carrier or diluent and which methods comprise administering to an animal, preferably a mammal including a human subject or a companion animal, such as a dog or cat, in need of such treatment, synergistic therapeutically effective amounts of a CRF antagonist and a RAS inhibitor.
A second preferred aspect of the instant invention relates to compositions and methods for treating hypertension, which compositions comprise synergistically effective amounts of a CRF antagonist and a RAS inhibitor, and a pharmaceutically acceptable carrier or diluent and which methods comprise administering to an animal, preferably a mammal including a human subject or a companion animal, such as a dog or cat, in need of such treatment, synergistic therapeutically effective amounts of a CRF antagonist and a RAS inhibitor.
The term xe2x80x9csynergisticxe2x80x9d as utilized herein means that the effect achieved with the methods and compositions of the instant invention is greater than the sum of the effects that result from methods and compositions comprising the inhibitors and antagonists of this invention separately and in the amounts employed in the methods and compositions hereof.
The term corticotropin releasing factor (CRF) antagonist refers to a compound having the ability to inhibit or reverse the deleterious effects of the presence of CRF. It is well known that CRF profoundly stimulates the pituitary-adrenalcortical axis and, in dysfunctional states, initiates behavioral, physiological and endocrine responses that are essentially identical to those observed when animals, including humans and companion animals, are subjected to a stressful environment. Therefore, CRF antagonists are known to have utility, inter alia, in the amelioration of certain stress-induced conditions including memory loss, mood alteration, depression, hypertension and the like.
The importance of CRF antagonists is set out h the literature, e.g., as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference, and a recent outline of the different activities possessed by CRF antagonists is found in Pharm. Rev., 43, 425-473 (1991). Such activity is readily determined by one skilled in the art according to standard assays including the methods described in Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1989) which determine the binding affinity of a test compound for a CRF receptor. The binding affinities for the active compounds, expressed as IC50 values, generally range from about 0.2 nanomolar to about 10 micromolar. A variety of additional compounds having utility as CRF antagonists are, or will be, known to those skilled in the art. For example, CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to certain peptides and pyrazolinones, respectively, the teachings of which are incorporated herein by reference.